screening for lung cancer

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03-05-12 Screening for lung cancer 1/25 www.uptodate.com/contents/screening-for-lung-cancer?view=print Official reprint from UpToDate ® www.uptodate.com ©2012 UpToDate ® Authors Mark E Deffebach, MD Linda Humphrey, MD Section Editors Robert H Fletcher, MD, MSc James R Jett, MD Deputy Editor H Nancy Sokol, MD Screening for lung cancer Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2012. | This topic last updated: mar 29, 2012. INTRODUCTION — Lung cancer is the leading cause of cancer-related death among men and women and second leading cause of cancer in the United States. Worldwide, lung cancer and lung cancer-related deaths have been increasing in epidemic proportions, largely reflecting increased rates of smoking [ 1,2 ]. In the year 2012, the American Cancer Society predicts that there will be approximately 226,160 new cases of lung cancer diagnosed and approximately 160,340 lung cancer-associated deaths in the US [ 3 ]. Worldwide, it is estimated that there were 1.4 million deaths in the year 2008 [ 4 ]. Unfortunately, 75 percent of patients with lung cancer present with symptoms due to advanced local or metastatic disease that is not amenable to cure [ 5 ]. Despite advances in therapy, five-year survival rates average approximately 16 percent for all individuals with lung cancer [ 6 ]. Prevention, rather than screening, is the most effective strategy for reducing the burden of lung cancer. The promotion of smoking cessation is essential, as cigarette smoking is felt to be causal in almost 90 percent of all lung cancer [ 1 ]. Progress in smoking cessation is now reflected in declining lung cancer rates and mortality in men in the US. However, the smoking rate in the US remains high at 24 percent and is increasing in many parts of the world [ 1 ]. A high percentage of lung cancer occurs in former smokers, since the risk for lung cancer does not decline for many years following smoking cessation [ 7-10 ]. Secondhand smoke exposure is common and is also associated with lung cancer [ 11 ]. (See "Secondhand smoke exposure: Effects in adults" .) Lung cancer is the leading cause of cancer-related death among women in the United States. Most lung cancer in women is attributed to smoking. However, a significant proportion of lung cancer in non-smoking women is attributed to other causes, including passive smoking [ 11 ]. Some [ 12,13 ], but not all [ 14 ] studies suggest that for any level of smoking, women are at higher risk of developing cancer than men. (See "Women and lung cancer" .) Screening for lung cancer will be reviewed here. General principles of screening, risk factors associated with the development of lung cancer, and techniques for smoking cessation are discussed separately. (See "Evidence- based approach to prevention" and "Overview of smoking cessation management in adults" and "Cigarette smoking and other risk factors for lung cancer" .) POTENTIAL FOR EARLY DETECTION — Clinical outcome for non-small cell lung cancer is directly related to stage at the time of diagnosis, ranging from over 60 percent five year survival for stage I disease, to less than 5 percent for stage IV disease (table 1 and figure 1 ) [ 15 ]. In addition, within early lung cancers (stage I) there is a relationship between tumor size and survival [ 16 ]. Available data are more limited for patients with small cell lung cancer, but also support an improved outcome when disease is diagnosed at an early stage. Many characteristics of lung cancer suggest that screening would be effective: high morbidity and mortality; significant prevalence (0.5 to 2.2 percent), identified risk factors allowing targeted screening for high risk, a lengthy preclinical phase, and evidence that therapy is more effective in early stage disease [ 17,18 ]. These observations have stimulated great interest in lung cancer screening for asymptomatic high-risk individuals,

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Page 1: Screening for Lung Cancer

03-05-12 Screening for lung cancer

1/25www.uptodate.com/contents/screening-for-lung-cancer?view=print

Official reprint from UpToDate® www.uptodate.com

©2012 UpToDate®

AuthorsMark E Deffebach, MDLinda Humphrey, MD

Section EditorsRobert H Fletcher, MD, MScJames R Jett, MD

Deputy EditorH Nancy Sokol, MD

Screening for lung cancer

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Mar 2012. | This topic last updated: mar 29, 2012.

INTRODUCTION — Lung cancer is the leading cause of cancer-related death among men and women and second

leading cause of cancer in the United States. Worldwide, lung cancer and lung cancer-related deaths have been

increasing in epidemic proportions, largely reflecting increased rates of smoking [1,2]. In the year 2012, the

American Cancer Society predicts that there will be approximately 226,160 new cases of lung cancer diagnosed

and approximately 160,340 lung cancer-associated deaths in the US [3]. Worldwide, it is estimated that there were

1.4 million deaths in the year 2008 [4].

Unfortunately, 75 percent of patients with lung cancer present with symptoms due to advanced local or metastatic

disease that is not amenable to cure [5]. Despite advances in therapy, five-year survival rates average approximately

16 percent for all individuals with lung cancer [6].

Prevention, rather than screening, is the most effective strategy for reducing the burden of lung cancer. The

promotion of smoking cessation is essential, as cigarette smoking is felt to be causal in almost 90 percent of all

lung cancer [1]. Progress in smoking cessation is now reflected in declining lung cancer rates and mortality in men

in the US. However, the smoking rate in the US remains high at 24 percent and is increasing in many parts of the

world [1]. A high percentage of lung cancer occurs in former smokers, since the risk for lung cancer does not

decline for many years following smoking cessation [7-10]. Secondhand smoke exposure is common and is also

associated with lung cancer [11]. (See "Secondhand smoke exposure: Effects in adults".)

Lung cancer is the leading cause of cancer-related death among women in the United States. Most lung cancer in

women is attributed to smoking. However, a significant proportion of lung cancer in non-smoking women is

attributed to other causes, including passive smoking [11]. Some [12,13], but not all [14] studies suggest that for

any level of smoking, women are at higher risk of developing cancer than men. (See "Women and lung cancer".)

Screening for lung cancer will be reviewed here. General principles of screening, risk factors associated with the

development of lung cancer, and techniques for smoking cessation are discussed separately. (See "Evidence-

based approach to prevention" and "Overview of smoking cessation management in adults" and "Cigarette smoking

and other risk factors for lung cancer".)

POTENTIAL FOR EARLY DETECTION — Clinical outcome for non-small cell lung cancer is directly related to

stage at the time of diagnosis, ranging from over 60 percent five year survival for stage I disease, to less than 5

percent for stage IV disease (table 1 and figure 1) [15]. In addition, within early lung cancers (stage I) there is a

relationship between tumor size and survival [16]. Available data are more limited for patients with small cell lung

cancer, but also support an improved outcome when disease is diagnosed at an early stage.

Many characteristics of lung cancer suggest that screening would be effective: high morbidity and mortality;

significant prevalence (0.5 to 2.2 percent), identified risk factors allowing targeted screening for high risk, a lengthy

preclinical phase, and evidence that therapy is more effective in early stage disease [17,18].

These observations have stimulated great interest in lung cancer screening for asymptomatic high-risk individuals,

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with a focus on imaging techniques and cytological analysis of sputum. The potential of screening to detect early

cancers may both increase the overall cure rate and allow more limited surgical resection to achieve cure. However,

screening will not accomplish these goals unless it takes place in the context of a multidisciplinary program to

assure that screening results are properly performed, interpreted, and followed-up, and that disease, when detected,

is managed appropriately.

Screening test attributes — The goal of screening is to identify asymptomatic patients with unrecognized disease

(pulmonary nodule) and to identify patients at increased risk (smoking, family, and occupational history).

The concept of cancer screening is based on the assumption that identifying and treating precancer or cancer in

asymptomatic individuals will prevent cancer or improve survival. This assumes that there is a treatable phase of

precancer or cancer that, if untreated, would progress, and that early treatment improves outcomes compared with

late treatment. While it is believed that most lung cancers progress to late stage cancer, it has not been proven that

all lung malignancies progress [19]. The ideal screening test would have high sensitivity for detecting disease prior

to development of advanced disease; high specificity; relative safety; acceptability to patients and physicians;

relative low cost; and, most importantly, would either reduce mortality, improve quality of life, or both [17].

The effectiveness of a screening test ideally is evaluated in randomized controlled trials to minimize methodological

biases. Several biases may impact screening studies: lead-time bias, length bias, and overdiagnosis (figure 2 and

figure 3 and figure 4). A fourth type of bias, volunteer bias, results because study volunteers may not be

representative of the general population; subjects may volunteer because they are concerned that they have

increased risk for the condition, or may volunteer because they are more than usually health-conscious and

therefore are at lower risk. The types of lung cancer most prevalent in screening trials (adenocarcinoma and

bronchioalveolar cell carcinoma) [20], may have a very long preclinical phase; lead-time bias could therefore result

in overdiagnosis [21]. These issues are discussed in detail separately. (See "Evidence-based approach to

prevention".)

Outcomes to be assessed — The success of lung cancer screening can be assessed using various outcome

measures, including cancer detection rates, stage at detection, survival, disease-specific mortality, and overall

mortality. For a lethal disease such as lung cancer, that requires invasive procedures for detection and treatment,

the most important outcomes to assess are disease-specific and overall mortality.

Potential harms of screening — While screening for lung cancer has the potential benefits of decreased

morbidity and mortality from lung cancer, it also has potential harms which may include:

Detection of abnormalities that require further evaluation, most of which are benign nodules. Evaluation may

involve needle biopsy and/or surgery, with associated morbidity and mortality [22,23]. In the National Lung

Screening Trial, as an example, over 53,000 high risk individuals were randomly assigned to low dose CT

scan or chest radiograph screening [24]. Among abnormal results (24.2 percent of CT scans and 6.9 percent

of radiographs), 96 percent were false positive (that is, did not lead to a diagnosis of lung cancer) and 11

percent of the positive results led to an invasive study.

Radiation from serial imaging in a screening program may add independently to the risk of developing

cancers, including lung cancer [25]. The increased radiation exposure associated with spiral CT scanning,

compared with plain radiographs, may further add to cancer risk [26]. Although the average effective dose of

radiation for the screening low-dose spiral CT was 1.5 mSv, compared to approximately 8 mSv for a

diagnostic chest CT scan, screening would require annual CT scans. Additional radiation exposure is

generated by further imaging studies ordered in the work-up of false-positive findings [23]. (See "Radiation-

related risks of imaging studies".)

Prolonged follow-up of nodules, often lasting several years, may cause anxiety related to fear of having lung

cancer. In one study of the impact of screening on quality of life measures, patients who had indeterminate

findings on an initial screen did report increased anxiety, although anxiety was only short-term and did not

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persist for the second round of screening [27].

Some cancers identified at screening may represent overdiagnosis. That is, cancers may be detected and

treated that, if never found, would not have affected morbidity or mortality during the patient’s lifetime. (See

'Overdiagnosis' below.)

SCREENING WITH CHEST X-RAY/SPUTUM CYTOLOGY — There have been at least seven large scale controlled

clinical trials of chest x-ray screening for lung cancer: six randomized controlled trials [28-42], and one non-

randomized controlled trial [43]. These studies began as early as 1960, and a 20-year follow-up analysis has been

published for one randomized trial [39,44,45]. No randomized trial has demonstrated a mortality benefit for chest x-

ray screening although there have been no studies comparing screening to no screening, only trials comparing

intense screening to less intense screening.

Biannual chest x-ray — The earliest trial, the Northwest London Mass Radiography Service, randomly assigned

55,000 male workers to receive chest x-rays every six months for three years, or a baseline and end-of-study chest

x-ray only. After three years, the annual mortality from lung cancer was 0.7 to 0.8 per 1000, and not different in the

two groups [29,30].

Annual sputum cytology plus chest x-ray — Two large randomized screening trials in the United States, the

Memorial-Sloan Kettering (MSK) Study and The Johns Hopkins Study, evaluated the incremental benefit of annual

sputum analysis to annual chest x-rays [28,35,40-42]. In both studies, all subjects (combined n >20,000) were

offered annual chest x-rays, with half randomly assigned to dual screening with sputum cytology; follow-up was five

to eight years. In both studies, no difference in lung cancer incidence or mortality was detected comparing the dual

screening and chest x-ray only groups. Neither of these studies specifically addressed the role of chest x-ray in

lung cancer screening.

More frequent screening

Czechoslovakian study — A study in Czechoslovakia of 6364 male smokers, aged 40 to 64 years, included

twice yearly sputum and chest x-ray examination for three years in the intervention group and annual x-ray in both

control and intervention groups in years three through six [37]. More cancers were found in the intervention group

(108 versus 82 in the control group), and more early stage cancer occurred in the intervention group, but there was

no difference in late stage cancer or cancer mortality [38].

Mayo Lung Project — The first North American trial to evaluate the value of intense screening with chest x-ray

and sputum cytology was the Mayo Lung Project, involving male smokers (n = 10,993) [32,33,39]. All participants

underwent prevalence screening (baseline) evaluation with chest x-ray and sputum cytology. Subjects were then

randomly assigned to the study group with a six year program of chest x-ray and sputum cytology every four

months (incidence screening), or to the control group receiving "usual care" and advised to have an annual chest x-

ray.

Prevalence screening identified 91 cancers (0.8 percent). After six years, 206 new cancers were identified in the

screening group, and 160 in the control group. After 20 years of follow-up, lung cancer death rates were significantly

higher in the screened group (4.4 versus 3.9 deaths per 1000 patient years). Significantly more early cancers were

detected in the screened cohort, but there was no reduction in late stage cancers.

This large randomized study has been the most influential in guiding prevention and public health recommendations

and is the most analyzed study of chest x-ray screening for lung cancer [46-49]. The study, however, has several

flaws, including "screening" chest x-rays in nearly half of the control group during the course of the study, with one-

third of the malignancies in the control group discovered by a screening chest x-ray. In addition, screening

compliance in the intervention group was only 75 percent. Finally, because the baseline (prevalence) screening

chest x-ray detected 91 cases of lung cancer, there was no completely unscreened group.

Overdiagnosis — There is no single explanation for the findings from the chest x-ray screening trials that have

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shown increased numbers of small early-stage lung cancers with screening but no associated reduction in mortality

over time. One possibility is overdiagnosis: that lung cancer screening detects cancers that would not otherwise

become clinically apparent. Whether overdiagnosis occurs with lung cancer is controversial. Autopsy studies show

low rates of unsuspected lung cancers among individuals who have died of other causes [50]. Clinical experience

suggests that clinically detected lung cancers are generally progressive.

However, twenty year follow-up data from the Mayo Lung Project do support the concept of overdiagnosis in lung

cancer screening [45]. In the absence of overdiagnosis and with successful randomization, the number of cases of

lung cancer (identified either by screening or clinical presentation) in both control and intervention groups should

equalize over time, as cancers in the control group become clinically apparent. Follow-up data in 1999 from 6101 of

the 7118 Mayo Lung participants who had been alive and without lung cancer at the end of the trial in 1983, found a

persistence of excess lung cancer in the screened group compared to controls (585 versus 500). Unless one

hypothesizes that the intervention itself increased the rate of lung cancer in the screened group, these data suggest

either overdiagnosis or inequalities between the randomized groups.

Overdiagnosis is difficult to quantify, but would be expected to have greater impact in screening programs where

subjects are at increased risk for other potentially life-threatening comorbidities, such as smokers [51]. The risk for

unnecessary invasive studies and therapy for "overdiagnosed" lung cancer might be greatest in this population. Only

randomized controlled trials of screening that evaluate lung cancer mortality as well as all cause mortality can

quantify the amount and impact of overdiagnosis.

Meta-analysis — All cause mortality was calculated in a meta-analysis, using data available from five of the

controlled trials on chest x-ray screening [52]. Pooled analysis comparing frequent with less frequent screening

found no significant impact of intensified x-ray screening on all-cause mortality; the identified summary relative risk

of death was 0.97 (95% CI 0.94-1.01).

PLCO Cancer Screening Trial — The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is a

large randomized trial (n = 154,942) evaluating the impact of screening individuals aged 55 through 74 for several

cancers, including lung cancer [53]. Screening for lung cancer consisted of a single posterior-anterior chest-x-ray at

baseline and annually for three years, while the control group received usual care. This study differs from prior chest

x-ray screening trials in several important aspects: the cohort includes men and women in equal numbers;

participants are not specifically high-risk (51.6 percent current or former smokers); and prevalence screening results

are included in the trial and analysis, allowing a true comparison of screening with no screening.

At the initial screening, 5991 (8.9 percent) of all chest-x-rays were abnormal, ranging from 11.0 percent in current

smokers to 8.0 percent in never smokers [54] After up to three rounds of annual screening (non-smokers did not

participate in the third screening round), participants were followed through 13 years, with a screening adherence of

86.6 percent at baseline and 79.0 to 84.0 percent years one through three [55]. There was no significant difference

in lung cancer incidence rates comparing screening and usual care groups (20.1 and 19.2 per 10,000 person-years,

RR 1.05, 95% CI 0.98-1.12). There was no difference in lung cancer mortality rates (RR 0.99, 95% CI 0.87-1.22) or

in stage of disease. Lung cancer incidence was higher among smokers than nonsmokers, but there was also no

difference in incidence or mortality comparing smokers who were in the screening or control groups. Only about 20

percent of the cancers occurring in the screening group were detected by screening. Thus annual screening with

chest x-ray, compared with usual care, did not reduce lung cancer mortality.

The lung cancer arm of the PLCO trial was designed to be completed in 2015. However, the monitoring board felt

that results would be unlikely to change with longer follow-up and that the current findings had public health

significance because of the recent report of the National Lung Screening Trial (NLST) that compared CT screening

with chest x-ray screening in a high-risk population. Data from the PLCO trial were also analyzed for a subset of

patients who would meet the criteria for the NLST. (See 'National Lung Screening Trial' below.)

Case-control studies — Six case-control studies, five conducted in Japan, have evaluated the role of chest x-ray

screening for lung cancer [56-62]. A 1950s case-control study, based on a tuberculosis screening program in which

chest x-ray was offered every one to two years to all adults in the former German Democratic Republic, showed no

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association between periodic chest x-ray and reduced lung cancer mortality [56]. In contrast, the five fair-quality

Japanese case-control studies suggest benefit with chest x-ray screening among men with smoking exposure and

women without direct smoking exposure or of mixed risk. Interpretation of these studies is limited by the potential

screening biases associated with non-randomized studies.

SCREENING WITH CHEST CT — The lack of a mortality benefit from chest x-ray screening and the refinement of

CT scanning techniques have led to the evaluation of low-dose helical CT for lung cancer screening [63]. New

multidetector CT scanners generate high-resolution imaging in a single breath hold with radiation exposure

significantly less than for diagnostic chest CT scanning. A study found that the overall average effective dose of low-

dose CT used in the National Lung Screening Trial was 2 mSv, compared with 7 mSv for a standard-dose diagnostic

chest CT examination [64]. (See 'National Lung Screening Trial' below.)

Results are available from one large randomized trial [24] and several observational cohort studies [65,66];

additional randomized trials are ongoing.

Randomized trials

National Lung Screening Trial — The National Lung Screening Trial (NLST), a randomized trial conducted

under the auspices of the National Cancer Institute, compared annual screening by low-dose chest CT scanning

with chest x-ray for three years in 53,454 high risk persons at 33 US medical centers [24,67,68]. Participants were

men and women 55 to 74 years of age with a history of at least 30 pack-years of smoking, and included current

smokers and those who had discontinued smoking within 15 years of enrollment.

The trial was stopped in November 2010 after an interim analysis found a statistically significant benefit for CT

scanning. At a median follow-up of 6.5 years, there were 645 cases of lung cancer per 100,000 person years (1060

cancers) in the CT group and 572 cases per 100,000 person years (941 cancers) in the chest x-ray group, resulting

in an incidence rate ratio of 1.13 (95% CI 1.03-1.23). Per 100,000 person years, there were 247 lung cancer deaths

in the CT group and 309 in the x-ray group, yielding a relative mortality reduction of 20.0 percent (95% CI 3.8-26.7).

Importantly, there was also a 6.7 percent (CI 1.2-13.6 percent) reduction in all-cause mortality in the CT group.

Positive findings were defined as a noncalcified nodule ≥4 mm on CT scan or any noncalcified nodule on x-ray. Over

all three screening rounds, 24.2 and 6.9 percent of participants in the CT and x-ray groups respectively had a

positive screen. The cumulative rate of false positive findings was high: 96.4 and 94.5 percent for CT and x-ray

screening respectively. Follow-up for false positive findings was at the discretion of the institution, but largely

entailed follow-up imaging. The rate of adverse events related to complications from the diagnostic work-up was low:

among participants with a positive finding, at least once complication occurred in 1.4 percent of the CT group and

1.6 percent of the x-ray group.

The rate of detection of lung cancer did not diminish between screening years, suggesting that ongoing screening

would be necessary. However, fewer stage IV cancers were observed in the CT group than the chest x-ray group

with the second and third screening rounds. Lung cancers detected by screening were mostly stage I or II (70

percent of CT-detected and 56.7 percent of x-ray detected), except for small cell cancers that accounted for less

than 10 percent of detected cancers. Chest CT identified a preponderance of adenocarcinomas.

Generalizability of these findings may be affected by the following factors: trial participants had a higher education

level and were younger than tobacco users identified in US census data; a low complication rate of follow-up

procedures may reflect the expertise at the participating academic centers; radiologic performance and

interpretation may not be representative of community-based radiology.

Since the control group in the NLST had screening with chest x-ray rather than usual care, findings of the Prostate,

Lung, Colorectal, and Ovarian (PLCO) trial, in which participants were randomly assigned to usual care or annual

chest radiography, are pertinent [55]. Results of the PLCO were analyzed for the subset of patients who would meet

criteria for participation in the NLST. There was no significant difference in mortality at six-year follow-up for the

PLCO high-risk subset who were assigned to chest x-ray screening or usual care (RR 0.94, 95% CI 0.81-1.10).

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In summary, the NLST demonstrated that CT screening reduced mortality in a high-risk population, compared to

screening by x-ray and, by inference from the PLCO data, compared to usual care. The number needed to screen

with low-dose CT to prevent one lung cancer death was 320 in the NLST. However, the cost of screening per life

saved is unknown but likely to be high, given the high (≈95 percent) false-positive rate leading to the need for

additional studies, the need for ongoing screening, and the relatively low absolute number of deaths prevented (73

per 100,000 person years). Modeling studies will be needed to determine actual cost-effectiveness.

Ongoing trials — As of 2010, eight randomized trials in addition to the NLST were in progress [69]. Among

them are the NELSON trial, the DANTE trial and the Danish Randomized Lung Cancer CR Screening Trial. Of

these, the only trial of large enough size to possibly show a mortality reduction is the NELSON trial.

The NELSON trial is a randomized CT-based lung cancer trial being conducted in the Netherlands and

Belgium; CT screening is being compared to no screening in 7557 current or former smokers [70]. The study

is powered to detect a 25 percent decrease in lung cancer mortality after ten years, as well as the effects of

screening on quality of life, smoking cessation, and an estimate of cost-effectiveness. Unlike other screening

studies, five-year lung cancer survivors, a group at very high risk of developing a new lung cancer, are also

eligible for enrollment. This is the only large-scale randomized trial to compare CT-screening to no screening.

Information is available at www.trialregister.nl/trialreg/admin/rctview.asp?TC=636.

A total of 90 subjects (1.2 percent) were found to have lung cancer after two rounds of screening [71]. The

proportion of stage I cancers in round one was 64 percent, lower than the 86 percent reported in the I-ELCAP

study, an observational study of low dose CT screening. (See 'Early Lung Cancer Action Project (ELCAP

and I-ELCAP)' below.) Follow-up for identified nodules was based on initial nodule volume and subsequent

change in size to limit invasive testing for false positive studies; using this protocol, 20 lung cancers were

found after two years of follow-up in the 7361 subjects who had initial negative screening.

CT screening results (indeterminate versus negative) did not significantly impact the smoking abstinence rate

among male smokers in this trial [72]. However, smokers with an indeterminate result on CT scanning

reported more quit attempts than those with a negative scan.

The DANTE trial, a randomized trial in Italy which enrolled 2472 male smokers age 60 to 74 years, is

designed to assess lung cancer-specific mortality over ten years, comparing five years of annual screening

by single slice spiral CT scan or annual clinical followup; the control group received baseline screening with

chest x-ray and sputum cytology [73]. At initial evaluation, lung cancer was found in 2.2 percent of the CT

group (71 percent stage I) and 0.67 percent of the controls (50 percent stage I) [74]. Fifteen percent of

subjects had an abnormal CT, and 4 percent underwent an invasive procedure. Benign pulmonary lesions

were found in 19 percent (6 of 32) of the patients who underwent thoracotomy.

Follow-up at an average of 33.7 months from enrollment, and after completion of the baseline and annual

screens, has been reported [75]. Lung cancer was found in 4.7 percent of patients who received CT

screening and 2.8 percent of controls. Although there were more stage I cancers in the screened group (54

compared to 34 percent), the number of advanced lung cancer cases and lung cancer mortality were the

same for both screened and control patients. The authors caution that these interim findings should not be

considered as definitive evidence that screening is ineffective but suggest that any effect may be smaller

than hoped for. It is possible that longer follow-up may be required to detect differences in disease-specific

mortality. Additionally, the trial size is small, compared to the NLST, and may not be of sufficient power to

detect a mortality difference.

The Danish Randomized Lung Cancer CT Screening Trial is another randomized trial of 4104 smokers (at

least 20 pack years) aged 50 to 70 years [76]. The trial is coordinated with the NELSON trial, so that final

results of both studies can be pooled to achieve an 80 percent power to detect a reduction in lung cancer

mortality of at least 25 percent. Baseline data from the Danish trial found a prevalence of lung cancer of 0.83

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percent (17 cases in 2052 participants), employing the algorithm from the I-ELCAP study for follow-up of

abnormal initial findings on CT scan, nine of the 17 cases were stage I. Of the 11 cases considered to be

surgically resectable, 8 were amenable to minimally invasive (VATS) technique. Initial results are anticipated

in 2012.

Observational studies

Early Lung Cancer Action Project (ELCAP and I-ELCAP) — The ongoing Early Lung Cancer Project

(ELCAP) reported results of baseline screening with low-dose spiral chest CT in 1000 asymptomatic patients who

had a ≥10 pack-year smoking history [77,78]. Each participant underwent both plain film and CT imaging; CT

detected malignant nodules in significantly more patients than plain films (2.7 versus 0.7 percent), but also detected

more nodules that ultimately proved benign (20.6 versus 6.1 percent). Twenty-seven lung cancers were identified,

with only one considered unresectable; 23 of the 27 cancers were stage I disease. Many benign lesions were

followed radiographically and did not require biopsy.

ELCAP has collaborated with lung cancer screening programs in 38 community and academic centers in five

countries to form the International ELCAP (I-ELCAP) [79]. Standard protocols for screening, follow-up imaging, and

evaluation of detected abnormalities, including follow-up CT scans, PET scans, and biopsies, were designated for

the I-ELCAP study. These evaluation algorithms depended heavily on follow-up imaging for detection of growth and

biopsy. Subsequent treatment of cancer, if detected, was at the discretion of patient and center.

I-ELCAP screened 31,567 asymptomatic participants with baseline CT scans; 27,456 received an annual screening

scan, and follow-up was performed according to the designated protocols. Positive CT results requiring further

workup were found in 13 percent (n = 4186) of initial scans and 5 percent (n = 1460) of annual scans. Lung cancer

was identified in 484 patients; 412 were stage I. The majority (405) of the cancers were detected at baseline

screening. This study confirms earlier observations that lung cancers detected through CT screening are early

stage. Because ELCAP and I-ELCAP are observational cohort studies without a control group, lead-time and

length-time bias cannot be controlled for, overdiagnosis cannot be estimated, and the results do not directly

address the effect of screening on lung cancer-specific and overall mortality [80].

Mayo Clinic CT study — Another large prospective observational study of low-dose CT screening for lung

cancer, conducted by the Mayo Clinic in conjunction with the National Cancer Institute, is following a cohort (n =

1520) of asymptomatic current or former smokers over age 50 years [81-84]. Baseline (prevalence) CT scans

identified one or more non-calcified nodules in 51 percent, with 1.7 percent diagnosed with primary lung cancer.

After three years of annual CT scanning, a total of 3356 non-calcified nodules were found in 73.5 percent of the

cohort; approximately 95 percent of the nodules were benign with clinical follow-up or surgical biopsy. Fifteen

surgeries were performed for benign disease.

Overall, a total of 68 primary lung cancers were documented in 66 subjects, 34 on annual (incidence) studies and 3

interval lung cancers not detected through annual screening. Of the incidence cancers, 61 percent were stage I and

33 percent presented at an advanced stage (III or IV).

Observational data versus modelled prediction — The above Mayo data were included as one arm of a

three arm study, also including data from CT scan observational studies conducted at centers in Milan and Florida

[22]. A total pooled group of 3246 asymptomatic high risk subjects underwent baseline and follow-up CT screening

for a median follow-up period of 3.9 years. The frequency of observed events related to lung cancer (any diagnosis,

diagnosis of advanced stage disease, surgical resection, or death) was compared with predictions based on two

validated models estimating risk of diagnosis and risk of death due to lung cancer derived from a similar high risk

population (over 18,000 individuals enrolled in a primary prevention trial for lung cancer [85]). The following results

were reported [22]:

144 study participants were diagnosed with lung cancer, compared to 44.5 predicted cases (RR 3.2, 95% CI

2.7-3.8).

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109 lung resections were performed, compared to 10.9 predicted (RR 10, 95% CI 8.2-11.9).

42 cases of advanced lung cancer were diagnosed, compared to a prediction of 33.4 to 51.2 cases,

depending on how patients lost to follow-up would be considered in the model. The difference between

observed and predicted rates is not significant.

38 deaths due to lung cancer were observed and 38.8 were predicted (RR 1.0, 95% CI 0.7 to 1.3).

Thus, CT scan did not decrease predicted lung cancer death or observed advanced lung cancer rates, but increased

the number of patients diagnosed with cancer and undergoing surgical resection. Estimated lung-cancer specific

survival for patients in this study was approximately the same as survival estimates in the I-ELCAP study. The

contrasting findings for this study compared to I-ELCAP most likely relate to the difference in primary outcome

measures: cancer survival (I-ELCAP) versus cancer mortality [86]. The limitations of this study were that it was not

a randomized control trial, and the sample size was such that it could not absolutely rule out as much as a 30

percent reduction in mortality with screening.

Patient-specific data from the Mayo Lung Project were also used in another modeling study, based on the Lung

Cancer Policy Model that incorporates cancer stage at time of diagnosis and non-cancer related mortality risks

[84]. Findings from this simulation were that annual screening with CT for four years, compared with no screening,

would lead to a decrease in lung cancer-specific mortality (relative decrease of 28 percent at six years and 15

percent at 15 years). All-cause mortality would also decrease (2 percent at 15 years), but the relative decrease

would be significantly lower than for cancer specific mortality because deaths from other causes (cardiovascular or

pulmonary in smokers) would occur, even if lung cancer deaths were prevented.

Other observational studies — The Pittsburgh Lung Screening Study (PLuSS), the largest single-institution

CT lung cancer screening study, reported outcomes within three years for 3642 high risk individuals who were to

have initial and one year follow-up lung CT screening [87]. Forty percent had noncalcified nodules on initial

screening and 55 percent of these patients had a subsequent diagnostic test (usually imaging) before the next

screening CT. Eighty patients were identified with lung cancer within three years of initial screening, including 53

with tumors observed at the first screening. Of the 69 with non small cell lung cancer, stage 1 disease was

diagnosed in 58 percent and stage 3 disease or higher in 36 percent.

One percent of the initial cohort had a major procedure (thoracotomy, video-assisted thorascopic surgery [VATS],

sternotomy, or mediastinoscopy) for a noncancer diagnosis, and one-third of all patients who underwent

thoracotomy or VATS (28 of 82) had a benign diagnosis. Subjects frequently underwent procedures prior to the

recommended interval for follow-up, despite protocols recommending specified imaging follow-up for CT findings not

considered to be high risk, with protocol reinforcement by nurses and consultation access to study physicians.

Long-term follow-up of this cohort will be useful in clarifying the natural history of various stages of screen detected

lung cancer.

There have been many reports of additional observational studies from Japan [88,89] and Europe [90-93]. Studies of

low dose CT and sputum cytology screening in Japan (>5000 prevalence screens and 8000 incidence screens in

both high and low risk participants) found 60 cancers; 55 were stage 1.

LUNG CANCER SCREENING IN WOMEN — Lung cancer is the leading cause of cancer-related death among

women in the United States [6]. Most lung cancer in women is attributed to smoking. However, a significant

proportion of lung cancer in non-smoking women is attributed to other causes, including passive smoking [11].

Some [12,13], but not all [14] studies suggest that for any level of smoking, women are at higher risk of developing

cancer than men. (See "Women and lung cancer".)

Women tend to develop adenocarcinoma of the lung disproportionately to men and adenocarcinoma is also found

more commonly among non-smokers [10]. This cell type tends to occur peripherally and may be more readily

detectable with chest x-ray and/or CT than other cell types. As a consequence, radiologic imaging and screening

for lung cancer may perform differently among women than men.

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Although several early studies focused primarily on men, newer and ongoing randomized trials have included both

men and women. Whether screening recommendations should be different for men and women remains to be

determined.

SYNTHESIZING THE AVAILABLE EVIDENCE — In summary, randomized controlled trials of chest x-ray based

screening and non-randomized cohort studies of CT based screening demonstrate:

Chest x-ray and CT screening frequently detect early stage asymptomatic lung cancers in screened

individuals.

CT screening is significantly more sensitive than chest x-ray for identifying small, asymptomatic lung

cancers. Chest x-ray screening does not reduce mortality from lung cancer.

Chest x-ray and CT screening have high rates of "false positive" (non-cancer) findings leading to additional

testing which usually includes serial imaging, but may include invasive procedures.

One large randomized trial of screening CT in high-risk individuals has demonstrated a lung cancer mortality

benefit of 20 percent, with all cause mortality reduced by 6.7 percent. However, the question of cost-

effectiveness is a major issue because of the significant costs associated with screening and, especially,

follow-up of the many false positive tests identified with CT screening in this trial. Additionally, relatively low

procedural complication rates in this trial may not be reproducible in other settings, and thus harms may be

greater than reported. These findings have generated conflicting opinions in the literature regarding the

initiation of screening [94,95].

If further analysis, including cost effectiveness analysis, determines a role for screening, issues of screening

frequency, appropriate population targets, criteria for a “positive” finding, and diagnostic follow-up protocols

remain to be addressed.

Cost-effectiveness — Decisions regarding implementation of a lung cancer screening program, based upon the

results of the NLST, should in part be based upon a cost-effectiveness analysis of a screening program. One

analysis, based upon a model designed prior to completion of the NLST, modeled the potential cost-effectiveness of

screening by CT scan for six different patient cohorts (differing ages and smoking histories) [96]. The modelers also

varied whether patients who underwent screening were more likely to quit smoking because of the opportunity for

smoking cessation intervention (nicotine replacement plus bupropion) or less likely to quit smoking because of

reassurance from a negative test result. Projections from this analysis were that CT screening might decrease lung

cancer mortality at 10 years by 18 to 25 percent, at a cost ranging from $126,000 to $269,000 per quality adjusted

life year (QALY). In comparison, the cost-effective ratios for colorectal and breast cancer screening are $47,700 and

$13,000 to $32,000 per QALY, respectively. Additionally, the model found that a smoking cessation program was

more cost-effective than CT screening alone or CT screening combined with smoking cessation.

Recommendations for screening by expert groups — Most expert screening groups have not yet incorporated

results from the NLST in their recommendations. Updated guidelines from the American Society of Clinical

Oncology (ASCO), the American Cancer Society, and the American College of Chest Physicians are anticipated in

2011 to 2012 [97].

The National Comprehensive Cancer Network (NCCN) issued guidelines for lung cancer screening in October 2011

[98]. These guidelines recommend annual low-dose CT scan screening for those at high risk; they recommend no

routine screening for moderate- or low-risk individuals. High risk was defined by the NCCN as age 55 to 74 years

with a 30 pack-year history of smoking and, if no longer smoking, smoking cessation within 15 years, or a 20 pack

year history of smoking with one additional risk factor (other than secondhand smoke exposure). Although the

guidelines note that the duration of screening is uncertain, they advise a minimum of three scans, so that

individuals initiating screening at age 74 would stop screening at age 76. The guidelines emphasize that lung

cancer screening should be done within the context of a multidisciplinary program (that may include radiology,

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pulmonary medicine, internal medicine, thoracic oncology, and/or thoracic surgery) to manage downstream testing.

Systematic screening with either CT or chest x-ray is not currently recommended by professional organizations

other than the NCCN (table 2). The US Preventive Services Task Force (USPSTF) concluded in 2004 that evidence

was insufficient to recommend for or against screening for lung cancer [44,99]. The USPSTF guidelines are also

undergoing review.

The International Association for the Study of Lung Cancer (IASLC) chartered an advisory committee in 2011 to

work with professional societies who are developing guidelines for screening [100]. The IASLC identified several

issues that need to be addressed in guideline development and implementation: defining the optimal population for

screening; determining the cost-effectiveness of screening; developing consistent CT screening protocols; defining

the optimal work-up for abnormal findings; defining optimal management of screen-detected nodules; determining

the optimal screening interval and number of screening rounds; and encouraging data collection and further research

to improve screening outcomes and limit complications. There was consensus that smoking cessation programs

need to be integrated into screening programs and that a lung cancer screening program should involve a

multidisciplinary team experienced in evaluation and management of early lung cancer.

Counseling for screening — Any program of lung cancer screening, if screening is undertaken, requires more

than CT capability. Screening should only be performed when the clinician and patient are committed to pursuing

follow-up investigations, including serial imaging and possible surgical lung biopsy.

Providers need to be experienced in the principles of screening and the management of small lung nodules. If these

components are in place and at-risk individuals (mostly through smoking and occupational exposure) are highly

motivated to be screened for lung cancer, the following points should be discussed with the patient before beginning

screening. Some have advocated formal informed consent including these points:

Smoking cessation is a more proven and powerful intervention for preventing death and complications from

lung cancer than screening. (See "Cigarette smoking and other risk factors for lung cancer".)

Lung cancer screening requires an ongoing commitment; cancers are detected on initial and annual studies,

and a single baseline study is insufficient.

The most likely "positive" result of screening is detection of benign nodules requiring further evaluation, and

this evaluation may require invasive studies, possibly even surgery.

For patients who would opt to be screened after appropriate counseling, and pending results of cost-effectiveness

analyses and ongoing randomized trials, we suggest screening with low dose helical CT scanning only for those

who meet all of the following criteria:

Are in general good health

Are at increased risk for lung cancer (similar to the risk of the group participating in the NLST trial)

Have access to centers whose radiologic, pathologic, surgical and other treatment capabilities in the

management of indeterminate lung lesions are equivalent to those in the NLST trial

Are able to manage the cost of annual screening and the possible need for subsequent evaluation of

abnormal findings. The role of insurance coverage in screening has not been determined following the NLST

results.

OTHER TECHNOLOGIES

Positron emission tomography — At least two studies evaluated annual low-dose CT followed by positron

emission tomography (PET) with fluorodeoxyglucose (FDG) for evaluating patients with noncalcified lesions ≥7 mm

in diameter, each with similar results [92,101].

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The more recent study enrolled 911 volunteers ≥50 years of age who had smoked for ≥20 pack-years [101].

Baseline CT identified 11 non-small cell lung cancers (NSCLC) and one small cell lung cancer (SCLC) (1.3 percent

prevalence); two NSCLCs were found in 424 subjects at annual follow-up study (0.5 percent incidence). All NSCLCs

were stage I. FDG-PET correctly diagnosed 19 of 25 indeterminate nodules. The sensitivity, specificity, positive

predictive value, and negative predictive value of FDG-PET for the diagnosis of malignancy were 69, 91, 90, and 71

percent, respectively. When a negative FDG-PET was followed three months later with a repeat CT, the negative

predictive value was 100 percent. If these results are validated by future studies, the simple algorithm employed

could have substantial implications for incorporation of PET imaging into large-scale screening programs.

Other approaches — Non-radiographic technologies may also contribute to the early detection of lung cancer.

Detection and treatment of small lung tumors (prior to radiographic visualization) may produce superior outcomes,

though the possibility of lead-time and other types of bias influencing the assessment of these technologies is

great. Outcome benefits must be thoroughly investigated prior to their widespread use [102].

These and similar techniques may also help identify people with significantly higher lung-cancer risk, in whom the

likelihood would be increased that radiographic studies would detect early stage lung cancer.

Technologies under investigation include:

Immunostaining or molecular analysis of sputum for tumor markers. As examples, p16 ink4a promoter

hypermethylation and p53 mutations have been shown to occur in chronic smokers before there is clinical

evidence of neoplasia [103-107].

Automated image cytometry of sputum [108].

Fluorescence bronchoscopy [109,110]. (See "Fluorescence bronchoscopy".)

Exhaled breath analysis of volatile organic compounds, which appear to be more common in patients with

lung cancer [111-113].

Genomic and proteomic analysis of bronchoscopic samples [114,115].

Serum protein microarrays for detecting molecular markers [116].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and

“Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade

reading level, and they answer the four or five key questions a patient might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the

Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the

10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with

some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these

topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on

“patient info” and the keyword(s) of interest.)

Basics topic (see "Patient information: Lung cancer screening (The Basics)")

Beyond the Basics topics (see "Patient information: Lung cancer prevention and screening (Beyond the

Basics)")

SUMMARY AND RECOMMENDATIONS

Lung cancer is the leading cause of cancer-related death. Prevention (promoting smoking cessation) is likely

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to have far greater impact on lung cancer mortality than is screening. (See 'Introduction' above.)

Detection of early-stage cancers through screening may allow more limited treatment and improved cancer

cure rates. The important outcome for cancer screening, however, is its impact on overall mortality. (See

'Outcomes to be assessed' above.)

Early trials of chest x-ray screening in males at high risk for lung cancer found no mortality benefit for x-ray

alone or x-ray plus sputum cytology. The Mayo Lung Project found more early cancers in the screened

cohort but no reduction in late-stage cancers and no reduction in mortality. Follow-up data suggest

overdiagnosis.

A large randomized trial (the PLCO) of single view chest x-ray found no decrease in lung cancer incidence or

mortality with screening. We recommend NOT screening for lung cancer with chest x-ray (Grade 1A). (See

'Screening with chest x-ray/sputum cytology' above.)

Lung cancer screening is a rapidly evolving field, with potential to significantly reduce the burden of lung

cancer. A large randomized trial (NLST) of annual low-dose CT screening in patients with a 30 pack-year

history of smoking, including those who quit smoking in the preceding 15 years, demonstrated a decrease in

lung cancer and all-cause mortality. Other large randomized trials are ongoing and guidelines from

professional organizations are undergoing revisions. (See 'Randomized trials' above and 'Recommendations

for screening by expert groups' above.)

All patients who smoke should be strongly counselled to quit smoking as the most-effective intervention to

reduce the risk of lung cancer. Patients who currently smoke or have a history of smoking should be advised

of the risks and benefits of screening for lung cancer (see 'Counseling for screening' above):

For patients in good health who are felt to have a risk for lung cancer at least as great as those in the

NLST and who have access to centers with radiologic, diagnostic, and treatment capabilities similar to

those in the NLST trial, and for whom the cost of screening is not an issue, we suggest annual

screening with low-dose helical CT (Grade 2B). Patients who wish to avoid the high risk of false-positive

results with such a program can reasonably choose not to be screened.

While awaiting the results of cost-effectiveness analyses and additional randomized trials of screening,

for patients at increased risk for lung cancer who do not meet the above criteria, we suggest not

screening (Grade 2C).

Plain chest x-ray screening has been shown to be ineffective for lung cancer screening.

Use of UpToDate is subject to the Subscription and License Agreement.

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79. International Early Lung Cancer Action Program Investigators, Henschke CI, Yankelevitz DF, et al. Survival ofpatients with stage I lung cancer detected on CT screening. N Engl J Med 2006; 355:1763.

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80. Welch HG, Woloshin S, Schwartz LM, et al. Overstating the evidence for lung cancer screening: theInternational Early Lung Cancer Action Program (I-ELCAP) study. Arch Intern Med 2007; 167:2289.

81. Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: five-year prospective experience.Radiology 2005; 235:259.

82. Swensen SJ, Jett JR, Sloan JA, et al. Screening for lung cancer with low-dose spiral computed tomography.Am J Respir Crit Care Med 2002; 165:508.

83. Swensen SJ, Jett JR, Hartman TE, et al. Lung cancer screening with CT: Mayo Clinic experience. Radiology2003; 226:756.

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85. Cronin KA, Gail MH, Zou Z, et al. Validation of a model of lung cancer risk prediction among smokers. J NatlCancer Inst 2006; 98:637.

86. Black WC, Baron JA. CT screening for lung cancer: spiraling into confusion? JAMA 2007; 297:995.

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89. Sone S, Li F, Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobilelow-dose spiral computed tomography scanner. Br J Cancer 2001; 84:25.

90. Diederich S, Wormanns D, Semik M, et al. Screening for early lung cancer with low-dose spiral CT:prevalence in 817 asymptomatic smokers. Radiology 2002; 222:773.

91. MacRedmond R, Logan PM, Lee M, et al. Screening for lung cancer using low dose CT scanning. Thorax2004; 59:237.

92. Pastorino U, Bellomi M, Landoni C, et al. Early lung-cancer detection with spiral CT and positron emissiontomography in heavy smokers: 2-year results. Lancet 2003; 362:593.

93. Novello S, Fava C, Borasio P, et al. Three-year findings of an early lung cancer detection feasibility study withlow-dose spiral computed tomography in heavy smokers. Ann Oncol 2005; 16:1662.

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104. Kersting M, Friedl C, Kraus A, et al. Differential frequencies of p16(INK4a) promoter hypermethylation, p53mutation, and K-ras mutation in exfoliative material mark the development of lung cancer in symptomaticchronic smokers. J Clin Oncol 2000; 18:3221.

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Topic 7566 Version 24.0

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GRAPHICS

TNM staging system for lung cancer (7th edition)

Primary tumor (T)

T1 Tumor ≤3 cm diameter, surrounded by lung or visceral pleura, without invasion moreproximal than lobar bronchus

T1a Tumor ≤2 cm in diameter

T1b Tumor >2 cm but ≤3 cm in diameter

T2 Tumor >3 cm but ≤7 cm, or tumor with any of the following features:

Involves main bronchus, ≥2 cm distal to carina

Invades visceral pleura

Associated with atelectasis or obstructive pneumonitis that extends to the hilar region butdoes not involve the entire lung

T2a Tumor >3 cm but ≤5 cm

T2b Tumor >5 cm but ≤7 cm

T3 Tumor >7 cm or any of the following:

Directly invades any of the following: chest wall, diaphragm, phrenic nerve, mediastinalpleura, parietal pericardium, main bronchus <2 cm from carina (without involvement ofcarina)

Atelectasis or obstructive pneumonitis of the entire lung

Separate tumor nodules in the same lobe

T4 Tumor of any size that invades the mediastinum, heart, great vessels, trachea,recurrent laryngeal nerve, esophagus, vertebral body, carina, or with separatetumor nodules in a different ipsilateral lobe

Regional lymph nodes (N)

N0 No regional lymph node metastases

N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes andintrapulmonary nodes, including involvement by direct extension

N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)

N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateralscalene, or supraclavicular lymph node(s)

Distant metastasis (M)

M0 No distant metastasis

M1 Distant metastasis

M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignantpleural or pericardial effusion

M1b Distant metastasis (in extrathoracic organs)

Stage groupings

StageIA

T1a-T1b N0 M0

StageIB

T2a N0 M0

Stage T1a,T1b,T2a N1 M0

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IIA T2b N0 M0

StageIIB

T2b N1 M0

T3 N0 M0

StageIIIA

T1a,T1b,T2a,T2b N2 M0

T3 N1,N2 M0

T4 N0,N1 M0

StageIIIB

T4 N2 M0

Any T N3 M0

StageIV

Any T Any N M1a or M1b

Adapted from: Goldstraw, P, Crowley, J, Chansky, K, et al. The IASLC Lung Cancer Staging Project:

Proposals for the revision of the TNM stage groups in the forthcoming (seventh) edition of the TNM

classification of malignant tumours. J Thorac Oncol 2007; 2:706.

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Overall survival by TNM grouping, NSCLC

Overall survival, expressed as median survival time (MST) and five-year survival,using the sixth edition of TNM staging system by (A) clinical stage and (B) pathologicstage. Reproduced with permission from: Goldstraw P, Crowley J, Chansky K, et al. The IASLC

Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the

forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007;

2:706. Copyright © 2007 Lippincott Williams & Wilkins.

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Lead-time bias

Image

Lead-time bias occurs when screening identifies disease at anearlier time but the time of death remains unchanged. In theabove diagram, lead-time bias for population B creates theimpression that patients diagnosed by screening have a longersurvival, although actual mortality is unchanged. Population Cdoes have improved survival, compared to the unscreenedpopulation A. O: onset of disease; Dx: diagnosis. Adapted from Fletcher

RF, Fletcher SW. Prevention. In: Clinical Epidemiology: The Essentials, 4th

ed. Lippincott Williams & Wilkins, Baltimore, 2005. Copyright © 2005

Lippincott Williams & Wilkins.

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Length-time bias

Length-time bias occurs when screening detects lessaggressive tumors. Cases that progress rapidly from onset(O) to symptoms and diagnosis (Dx) are less likely to bedetected during a screening examination. Thus, patientswhose tumors are identified by screening may appear to havebetter outcomes, but their tumors may differ biologically fromthe general cohort of patients with that cancer. Adapted with

permission from: Fletcher, RH, Fletcher, SW. Prevention. In: Clinical

Epidemiology - The Essentials, 4th ed. Lippincott Williams & Wilkins,

Baltimore 2005. p. 147 - 167.) Copyright © 2005 Lippincott Williams and

Wilkins.

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Overdiagnosis in cancer screening

Overdiagnosis occurs when cancers that are non-progressive,as well as some very slow growing cancers, are detected byscreening but will never cause clinical harm during a patient'slifetime. Overdiagnosis is an extreme form of length-time bias. Originally reprinted from Welsh, HG. Should I be tested for cancer? Maybe

not and here's why. Berkeley and Los Angeles, California: University of

California Press, 2004. Adapted with permission from: Fletcher, RH,

Fletcher, SW. Prevention. In: Clinical Epidemiology - The Essentials, 4th

ed. Lippincott Williams & Wilkins, Baltimore 2005. p. 147-167. Copyright

© 2005 Lippincott Williams & Wilkins.

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Guidelines for lung cancer screening

Organization Recommendation Year

US PreventiveServices TaskForce

Evidence is insufficient to recommend for or against screeningasymptomatic persons for lung cancer with either low-dosecomputerized tomography, chest x-ray, sputum cytology, or acombination of these tests.

2004

American Collegeof ChestPhysicians

Recommends against the use of low-dose CT, chest radiographs,or sputum cytology for lung cancer screening, including smokersor others at high risk, except in the context of a clinical trial.

2007

American CancerSociety

Informed individual decision-making; if testing is chosen, spiralCT should be performed only in centers with multidisciplinaryspecialties experienced in screening and treatment.

2006

AmericanAcademy ofFamily Physicians

Recommends against the use of chest x-ray and/or sputumcytology in asymptomatic persons.

1997

Canadian TaskForce on thePeriodic HealthExamination

Recommends against the use of chest x-ray in asymptomaticpersons. Evidence is insufficient to recommend for or againstscreening with spiral CT in asymptomatic persons.

2003

NationalComprehensiveCancer Network

Recommends annual low-dose CT scan screening for high-riskindividuals (age 55 to 74 years with 30 pack-year history ofsmoking or 20 pack-year history with an additional risk factor).

2011

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